Combining Bacteriophage-Mediated Decolonization with Microbial Engraftment to Foster Sustained Supragingival Microbiome Modulation for Enhanced Anti-Cariogenic Therapy

将噬菌体介导的去定植与微生物植入相结合，促进龈上微生物组的持续调节，以增强抗龋齿治疗

• 批准号: 10080641
• 负责人: Michael Sandor Koeris
• 金额: $ 25.66万
• 依托单位: VULCAN BIOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2021-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080641
• 关键词: Abscess; Acids; Adherence; Adolescent; Adult; Affect; Awareness; Bacteria; Bacteriophages; Biological; Caries prevention; Cessation of life; Child; Chronic Disease; Cleaved cell; Dental; Dental Enamel; Dental caries; Dentures; Development; Dietary Sugars; Disease; Engineering; Engraftment; Enzymes; Esophagus; Etiology; Eukaryotic Cell; Fluorides; Fostering; Glucans; Head Cancer; Head and neck structure; Health; Human; Immune; In Vitro; Inflammatory Bowel Diseases; Ingestion; Knowledge; Lactobacillus; Libraries; Light; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of pancreas; Measures; Mediating; Methods; Microbial Biofilms; Modeling; Neck Cancer; Nutrient; Oral; Oral candidiasis; Oral cavity; Pain; Pathogenesis; Periodontitis; Phase; Polysaccharides; Population; Prevalence; Probiotics; Production; Productivity; Quality of life; Rattus; Resistance; Role; Saliva; Salivary; Sampling; Sepsis; Serotyping; Source; Stomatitis; Streptococcus mutans; Testing; Tissues; Virulent; Virus; Work; antimicrobial peptide; arm; base; clinically relevant; comorbidity; dental agent; dental biofilm; effectiveness testing; experimental study; improved; malignant mouth neoplasm; member; microbial; microbial community; microbiome; novel; nuclease; oral microbial community; oral microbiome; prebiotics; prevent; small molecule; subgingival biofilm; synthetic biology

Abstract Vulcan Biologics is developing a platform that harnesses the power of synthetic biology to enable persistent and stable modulation of the oral microbiome for the prevention of dental caries. Caries are characterized by the acidification and degradation of tooth enamel when dietary sugars come into contact with dental biofilms (plaque). Dental caries is the most prevalent chronic disease in humans, affecting 42% of children, 59% of adolescents, and 92% of adults in the U.S. It can be accompanied by serious comorbidities and complications, including pain, abscesses, dental sepsis, and even death. Caries also contribute to diminished quality of life and account for an estimated $5.4 billion in lost productivity each year. Current methods to prevent caries, including brushing/flossing and fluoride applications, have done little to reduce the overall prevalence of caries in the population in the last decade, thus necessitating the development of more effective measures. There is an increasing awareness of the role of the oral microbiome in dental caries pathogenesis. Streptococcus mutans is a naturally occurring member of the oral microbiota and the principal etiological agent of dental decay in humans. Vulcan Biologics proposes a tripartite approach for the persistent and stable reprogramming of the oral microbiome to reduce or eliminate the prevalence of S. mutans. This approach is based on combining the application of bacteriophages—viruses that exclusively target bacteria but do not affect eukaryotic cells—with selected bacteria providing a probiotic effect and nutrients (prebiotics) that are specific to the protective probiotic bacteria. This decolonization/recolonization (Decon-Recon) strategy has the potential to succeed where previous attempts to provide effective and enduring modulation of the microbiome have failed, namely in overcoming the resistance of established microbial communities to the permanent engraftment of newcomers. To demonstrate the feasibility of this approach, in this Phase I project, Vulcan Biologics will: 1) establish and characterize bacterial and phage libraries, including isolating novel virulent phages from saliva samples and analyzing their host ranges; 2) engineer virulent phages with antimicrobial peptides and biofilm-degrading enzymes to improve S. mutans killing ability; and 3) establish a biofilm model and assess S. mutans reduction resulting from phage treatment alone, probiotic treatment alone, or their combination. This will test the effectiveness of the first two steps in our 3-part approach and pave the way for Phase II work to evaluate the efficacy upon integration of all 3 steps (i.e., providing a prebiotic) and in a rat model. Ultimately, this approach promises to provide a long-term and persistent method to prevent dental caries.

抽象的 Vulcan Biologics 正在开发一个平台，利用合成生物学的力量来实现持久和 稳定调节口腔微生物群以预防龋齿的特点是。 当膳食糖与牙齿生物膜接触时，牙釉质酸化和降解 （牙菌斑）是人类最常见的慢性疾病，影响 42% 的儿童、59% 的儿童。 青少年和美国 92% 的成年人可能伴有严重的合并症和并发症， 包括疼痛、脓肿、牙科败血症，甚至死亡也会导致生活质量下降。 据估计，目前预防龋齿的方法每年造成 54 亿美元的生产力损失。 刷牙/使用牙线和氟化物的应用，对降低龋齿的总体患病率几乎没有什么作用。 人口在过去十年中不断增加，因此有必要制定更有效的措施。 人们越来越认识到口腔微生物组在龋齿发病机制中的作用。 口腔微生物群中天然存在的成员，也是人类蛀牙的主要腐烂剂。 Vulcan Biologics 提出了一种三方方法来持久稳定地重新编程口腔 微生物组来减少或消除变形链球菌的流行这种方法基于结合以下方法。 噬菌体（针对细菌但不专门影响真核细胞的病毒）的应用 精选细菌提供益生菌作用和保护性益生菌特有的营养物质（益生元） 这种去定植/再定植（Decon-Recon）策略有可能在以前的方法中取得成功。 提供有效和持久的微生物组调节的尝试已经失败，即克服 已建立的微生物群落对新来者的永久植入的抵抗力。 为了验证这种方法的可行性，在这一阶段的项目中，Vulcan Biologics 将：1) 建立细菌并对其进行表征 和噬菌体库，包括从唾液样本中分离新型剧毒噬菌体并分析其宿主 范围；2）用抗菌肽和生物膜降解酶改造毒力噬菌体以改善链球菌。 变形链球菌杀灭能力；和3)建立生物膜模型并评估噬菌体导致的变形链球菌减少 单独治疗、单独益生菌治疗或它们的组合这将测试前两者的有效性。 我们的三部分方法中的步骤，为第二阶段工作铺平道路，以评估整合所有内容后的功效 3 个步骤（即提供益生元），最终在大鼠模型中，这种方法有望提供长期效果。 以及持久预防龋齿​​的方法。